This invention relates generally to electrotransport drug delivery. More particularly, the invention relates to a novel method of making a new type of drug reservoir for incorporation into an electrotransport drug delivery system. The invention additionally relates to new drug reservoirs, and to electrotransport drug delivery systems containing these reservoirs.
The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniencesxe2x80x94e.g., gastrointestinal irritation and the likexe2x80x94are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
However, many drugs are not suitable for passive transdermal drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body through intact skin. The method of the invention relates to such an administration technique, i.e., to xe2x80x9celectrotransportxe2x80x9d or xe2x80x9ciontophoreticxe2x80x9d drug delivery.
Herein the terms xe2x80x9celectrotransportxe2x80x9d, xe2x80x9ciontophoresisxe2x80x9d, and xe2x80x9ciontophoreticxe2x80x9d are used to refer to the transdermal delivery of pharmaceutically active agents by means of an applied electromotive force to an agent-containing reservoir. The agent may be delivered by electromigration, electroporation, electroosmosis or any combination thereof. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically induced osmosis. In general, electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species. During the electrotransport process, certain modifications or alterations of the skin may occur such as the formation of transiently existing pores in the skin, also referred to as xe2x80x9celectroporationxe2x80x9d. Any electrically assisted transport of species enhanced by modifications or alterations to the body surface (e.g., formation of pores in the skin) are also included in the term xe2x80x9celectrotransportxe2x80x9d as used herein. Thus, as used herein, the terms xe2x80x9celectrotransportxe2x80x9d, xe2x80x9ciontophoresisxe2x80x9d and xe2x80x9ciontophoreticxe2x80x9d refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Systems for delivering ionized drugs through the skin have been known for some time. British Patent Specification No. 410,009 (1934) describes an iontophoretic delivery device which overcame one of the disadvantages of the early devices, namely, the need to immobilize the patient near a source of electric current. The device was made by forming, from the electrodes and the material containing the drug to be delivered, a galvanic cell which itself produced the current necessary for iontophoretic delivery. This device allowed the patient to move around during drug delivery and thus required substantially less interference with the patient""s daily activities than previous iontophoretic delivery systems.
In present electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient""s skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Existing electrotransport devices additionally require a reservoir or source of the pharmaceutically active agent which is to be delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
Thus, an electrotransport device or system, with its donor and counter electrodes, may be thought of as an electrochemical cell having two electrodes, each electrode having an associated half cell reaction, between which electrical current flows. Electrical current flowing through the conductive (e.g., metal) portions of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid-containing portions of the device (i.e., the drug reservoir in the donor electrode, the electrolyte reservoir in the counter electrode, and the patient""s body) is carried by ions (ionic conduction). Current is transferred from the metal portions to the liquid phase by means of oxidation and reduction charge transfer reactions which typically occur at the interface between the metal portion (e.g., a metal electrode) and the liquid phase (e.g., the drug solution). A detailed description of the electrochemical oxidation and reduction charge transfer reactions of the type involved in electrically assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard and L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley and Sons, 1980).
The present invention is directed to novel polymeric foam matrix drug reservoirs for use in conjunction with an electrotransport drug delivery system and methods of making these new reservoirs. In contrast to methods for making prior drug reservoirs for use in such systems and in contrast to prior drug reservoirs, the present method provides a reservoir that enables smaller quantities of drug to be loaded into the system. This is an important consideration with respect to more costly drugs, such as peptides and proteins produced from genetically engineered cell lines, and/or highly potent drugs for which a small dosage is efficacious. With such drugs, it is desirable to decrease the amount of drug loaded into the reservoir.
Typically, for drug delivery using transdermal drug delivery devices it is preferred that drug flux is independent of the concentration of drug in the reservoirs. Decreasing drug loading has the effect of decreasing the concentration of drug in the reservoir to a point where drug flux becomes dependent on reservoir drug concentration. Thus, it is desirable to maintain higher drug concentration in the drug reservoir.
Although it is possible to reduce both the drug loading and the volume of the reservoir, thereby maintain the drug concentration above a level required for concentration-independent drug flux, there are limits on how small the drug reservoir may be. For example, if the volume of the donor reservoir is reduced by decreasing the skin contact area the potential for skin irritation, i.e., irritation caused by the applied electric current and/or the drug being delivered, increases. If the volume of the donor reservoir is reduced by decreasing the thickness of the reservoir, the potential for electrical shorting between the electrodes and the skin increases. In addition, thinner reservoirs are inherently more difficult to manufacture with precise uniformity.
Thus, there is a need for a method of reducing electrotransport donor reservoir drug loading without reducing reservoir size or volume.
Accordingly, it is a primary aspect of the invention to provide a method for preparing a novel drug reservoir for use in conjunction with an electrotransport drug delivery system, which overcomes the above-mentioned limitations in the art.
It is another aspect of the invention to provide a method for making a novel therapeutic agent-containing polymeric foam reservoir having a predetermined volume for use in electrotransport drug delivery, which method involves foaming a polymeric matrix that contains a cross-linkable polymer.
It is still another aspect of the invention to provide such a method which involves foaming an admixture of a therapeutic agent and a polymeric matrix that contains a cross-linkable polymer.
It is a further aspect of the invention to provide such a method which involves the incorporation of air, carbon dioxide, oxygen, nitrogen, noble gases, or other gas or gases into a polymeric matrix such that the resulting therapeutic agent-containing polymeric reservoir has a relatively high surface area with respect to the amount of polymeric matrix used.
It is still a further aspect of the invention to provide a method for preparing a therapeutic agent-containing polymeric foam reservoir capable of transdermally delivering peptides, proteins, or fragments thereof.
It is still another aspect of the invention to provide an electrotransport drug delivery device capable of cost-effectively delivering peptides, proteins, or fragments thereof.
Additional aspects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment of the invention, then, a method is provided for making a therapeutic agent-containing polymeric reservoir having a predetermined volume for incorporation into an electrotransport agent delivery system adapted to deliver the therapeutic agent by electrotransport through an animal body surface. The method comprises placing a predetermined amount of the therapeutic agent in a polymer matrix to produce a drug-containing polymer matrix, foaming the polymer matrix with a gas, and cross linking the foamed matrix to produce a polymeric closed cell foam reservoir matrix having a predetermined pore volume. Once the foamed matrix is hydrated with a liquid solvent used to solubilize the therapeutic agent, the closed foam cells contain the gas and are substantially free of the therapeutic agent and the liquid solvent.
In a preferred embodiment of the invention, a method is provided for preparing a drug reservoir to be incorporated in an electrotransport drug delivery device, the method comprising foaming a polymeric mixture of polyvinyl alcohol by rapidly stirring the mixture in a selected atmosphere to produce a polymeric foam. A therapeutic agent is added to the polymeric foam, and the drug-containing foam is frozen and then allowed to warm to ambient temperature. Alternatively, the polymeric foam may be frozen and thawed, and a therapeutic agent added to the polymeric foam at a later time, but prior to its use in conjunction with the electrotransport drug delivery device.
In another embodiment of the invention, a therapeutic agent-containing polymeric reservoir having a predetermined volume is provided which comprises a chemically cross-linked polymeric closed-cell foam matrix containing a predetermined amount of the therapeutic agent and a predetermined volume percent of closed foam cells.
In still another embodiment of the invention, a therapeutic agent-containing polymeric reservoir having a predetermined volume is provided which comprises a polymeric closed-cell foam matrix cross-linked by exposure to actinic radiation and which contains a predetermined amount of the therapeutic agent and a predetermined volume percent of closed foam cells.
In a further embodiment of the invention, an electrotransport drug delivery system is provided which incorporates the aforementioned polymeric foam reservoir. The system contains a donor electrode, a counter electrode, a source of electrical power, and the polymeric reservoir containing the therapeutic agent to be delivered, typically present as part of the donor electrode.